Lung Cancer Highlights from ASCO 2016

More than 30,000 oncology professionals and patients gathered in Chicago from June 3–7 for the Annual Meeting of the American Society of Clinical Oncology. Credit: dronepicr, CC BY 2.0

This year, the Annual Meeting of the American Society of Clinical Oncology (ASCO) did not produce any truly groundbreaking revelations about new treatments for lung cancer. However, researchers did report quite a few positive findings, and some disappointing ones. I have summarized some of the more prominent presentations below.

EGFR-mutant NSCLC

At the meeting, which took place from June 3–7 in Chicago, a special panel of experts generally agreed that there is not much difference between the first-generation EGFR inhibitor drugs erlotinib (Tarceva), gefitinib (Iressa), and afatinib (Gilotrif). This interchangeability suggests there are several good choices for first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC).

Another hot topic was the use of liquid biopsies. The same panel of experts discussed the role of liquid biopsies in diagnosis and treatment follow-up, with a particular focus on EGFR-mutant lung cancer. The U.S. Food and Drug Administration (FDA) had already approved the cobas EGFR mutation liquid biopsy test earlier this month, but the panel was still divided over whether testing tumor DNA isolated from blood is a good enough substitute for a standard tumor biopsy. Obviously, liquid biopsies are no substitute for an initial diagnostic biopsy, but the availability of this technology for follow-up is a great advantage.

However, the panel had no disagreements about third-generation EGFR inhibitors. Several promising ones are in clinical trials, and trial results presented at the ASCO conference showed these drugs’ activity in tumors with an EGFR T790M mutation (T790M frequently arises as a resistance mutation in the EGFR gene after treatment with erlotinib or other inhibitors). However, newer T790M inhibitors will have a tough time competing with osimertinib (Tagrisso). The FDA approved osimertinb late last year, and it has excellent activity that will be hard to beat. Osimertinib is also active in leptomeningeal disease, a dangerous condition in which metastatic cells grow inside the spinal and meningeal space.

NSCLC with ALK translocation

Brigatinib, a second-generation ALK inhibitor, was reported at the meeting to be highly active in ALK-translocated NSCLC. In a clinical trial, 72% of patients who stopped responding to the first FDA-approved ALK inhibitor, crizotinib (Xalkori), had objective responses to brigatinib. The median duration of responses in this group was 14.5 months, and longer in patients who had not received crizotinib previously. Most encouragingly, patients with brain metastases had a similarly high rate of responses to brigatinib (67%).

NSCLC with ROS translocation

ROS translocations are relatively rare in adenocarcinoma of the lung, and are treated with crizotinib, which the FDA just approved for this molecular subtype in March of this year. In a clinical trial presented at the ASCO meeting, a new inhibitor of translocated ALK and ROS, PF-06463922 (lorlatinib), showed promising activity in patients with either of the two alterations, including patients who had received prior crizotinib and developed resistance. Again, following a noticeable pattern for ALK and ROS inhibitors, at least half of the patients with brain metastases in the trial responded to lorlatinib.

BRAF-mutant NSCLC

Another relatively rare subtype of adenocarcinoma, BRAF-mutant NSCLC, usually compels oncologists to consider treatment with vemurafenib (Zelboraf), a mutant BRAF inhibitor, even though it isn’t FDA-approved for this use. Now, a combination of dabrafenib (Tafinlar) and trametinib (Mekinist), which is used to treat BRAF-mutant melanoma, has shown an objective response rate of 63% in BRAF-mutant lung cancer, with a median duration of 9 months. This is most likely a better response rate than observed previously with vemurafenib alone.

Immunotherapy

As they have for several years, immune checkpoint drugs again dominated the ASCO meeting, in lung cancer perhaps particularly so. A number of reports on the activity of nivolumab (Opdivo, clinical trials CheckMate-057 and 017), pembrolizumab (Keytruda), and nivolumab combined with ipilimumab (Yervoy) in lung cancer generally extended and validated previous findings on the superiority of these drugs compared to standard chemotherapy as a second-line treatment. The combination of nivolumab and ipilimumab showed the best rate of responses. This combination also showed promising results as a first-line treatment (CheckMate-227); responses were seen in 27% of never-smokers and in 46% of smokers.

The combination of nivolumab and ipilimumab worked better in small cell lung cancer (SCLC) patients as well, with a higher rate of responses than was seen with nivolumab alone (20% versus 10%, respectively). Responses also lasted longer. However, these improvements came with a higher burden of toxicities (side effects). Two large phase III clinical trials are planned to further demonstrate the efficacy of the combination in SCLC.

High expectations for combinations of immune drugs with other types of drugs or treatments were not fulfilled at ASCO 2016 because these trials, though numerous, are still very new. A noteworthy report described a trial in which Keytruda was combined with standard chemotherapy (carboplatin and pemetrexed) as a first-line treatment for NSCLC, giving an objective response rate (ORR) of 71%. Combining Keytruda with other chemotherapy drugs (carboplatin and taxol with or without bevacizumab) produced an ORR of close to 50%. It remains to be seen whether these responses are durable; time might tell.

Many new immune drugs exist, and two ASCO reports presented findings from early phase I clinical trials. The 4-1BB agonist PF-05082566 (utomilumab) and the OX40 agonist MOXR0916 were shown to be safe, but only utomilumab had promising activity in a variety of cancer types: utomilumab combined with pembrolizumab produced an objective response in 6 out of 23 patients (26%) with various cancers, including two with lung cancer. This is a new drug to watch closely.